PB2494: ADMINISTRATION OF GRANULOCYTE-MACROPHAGE COLONY-STIMULATING FACTOR ENHANCED CAR T-CELL EXPANSION AND CELLULAR IMMUNITY RECOVERY WITHOUT INDUCING CYTOKINE RELEASE SYNDROME
Authors: Ying Jiang, Dan Feng, Chun Wang, Yanlei Zhang, Chuxian Zhao, Su LI, Youwen Qin, Alex H. Chang, Jun Zhu
Journal: HemaSphere (2023)

Topic: 25. Gene therapy, cellular immunotherapy and vaccination - Clinical Background: Neutropenia and cytokine release syndrome (CRS) are two major toxicities of Chimeric antigen receptor T (CAR T) cell therapy. Granulocyte-macrophage colony-stimulating factor (GM-CSF) is an ideal candidate treatment for neutropenia except for its potential aggravation of CRS. We hypothesized that the optimal timing of supplemental with GM-CSF in a shortage of host immunity and CAR T-cell was chosen as avoidance of CRS. Aims: We explored GM-CSF as a therapeutic intervention aimed at alleviating neutropenia, promoting cellular immunity recovery, as well as enhancing CAR T-cell expansion in patients. In this cohort, nine patients undergone different CAR T-cell therapies have been treated with GM-CSF, to assess the safety and efficacy of GM-CSF intervention post-CAR T-cell therapy while circulating CAR T-cell declined. Methods: Nine patients were enrolled in cohort from July 2021 and November 2021 to receive GM-CSF therapy whose clinical characteristics are shown in Table 1. GM-CSF was subcutaneous administrated. The indication for initiation of GM-CSF therapy was patients who display moderate neutropenia with absolute neutrophil counts (ANC) <1500 cells/mm3. The indication for termination of GM-CSF therapy, was either when their ANC levels had reached to 3000-5000 cells/mm3. All patients started GM-CSF at 100ug daily. After 3 days, the dose of GM-CSF in two patients was escalated to 200ug daily because no increment in WBC was observed. Results: The median duration of GM-CSF intervention was 15 days (4-30). The median interval between start of GM-CSF and CAR T-cell infusion was 20 days (8-126) while the number of CAR T-cell in peripheral blood (PB) dropped to 20.3% (0-59.7) of pre-GM-CSF peak except for patient #2 who had no CAR T-cell expansion before GM-CSF administration. The median duration of GM-CSF intervention was 15 days (4-30). Seven out of nine patients (77.8%) experienced CAR T-cell expansion in PB during GM-CSF usage. The median baseline and peak CAR T cells count in PB of the seven patients with CAR T-cell expansion were 0.85×106/L (0-50.9) and 6.06×106/L (1.43-112.55). The peaks of CAR T-cell levels appeared in day 7(2-11) following the initiation of GM-CSF administration with increases of 2.84×106/L (0.38-61.65). In addition, although no increased CAR T-cell count in PB was observed in patients #8 and #9, the percentage of CAR T-cell in cerebrospinal fluid of patient #8 increased from 4.43% to 35.78% at day 6 and dropped to 1.38% at day 10 meanwhile GM-CSF was administrated. Also, increased white blood cells in PB was observed in all patients. The median onset and duration time of WBC recovery were 9 (1-14) and 17(3-53) days. Moreover, the increment of WBC, neutrophil, lymphocyte and CD3-CD16+CD56+ natural killer cell in PB was observed. In addition, no CRS or fatal infection occurred during GM-CSF treatment. Summary/Conclusion: Overall, we explored the timing of GM-CSF administration to play a role in CAR T-cell expansion and cellular immunity recovery without inducing CRS which facilitates to increase durable complete responses and decrease infection rates after CAR T therapy. On the basis of these results, this approach may improve the overall safety and efficacy of CAR T therapies for cancer patients and may eliminate the need for robust anti-infection treatment. Therefore, this study provides evidence for the clinical feasibility of combining CAR T-cell therapy with the GM-CSF to treat neutropenia patients with concomitant declination of circulating CAR T-cell.Keywords: CAR-T, Cytokine release syndrome, Neutropenia, Infection